Chemokines are a superfamily of mostly small, secreted proteins that function in leukocyte trafficking, recruiting, and recirculation. These proteins also play an important role in many pathophysiological processes, including allergic responses, chemotaxis, infectious and autoimmune diseases, angiogenesis, inflammation, tumor growth, tumor metastasis, and hematopoietic development. All chemokines signal through seven transmembrane domain G-protein coupled receptors (“GPCRs”). (See Baggiolini et al., Ann. Rev. Immunol. 15:675 (1997); Schall, in The Cytokine Handbook, 2nd ed. Thomson, A. editor, Academic Press, New York, pages 418-60 (1994); Murphy et al., Annu. Rev. Immunol. 12:593 (1994)). The various chemokine receptors are known to have overlapping chemokine ligand specificities. At least seventeen chemokine receptors are known. For many of these receptors, several different chemokines can signal through the same receptor. The finding that HIV viruses use some chemokine receptors as co-receptors for entry into cells has generated an increased interest in chemokine receptor research. (See, Deng et al., Nature 381:661 (1996); Alkahatib et al., Science 272:955 (1996); Broder, J. Leukocyte Biol. 62:20 (1997)).
Chemokines are divided into subfamilies based on conserved amino acid sequence motifs. Most chemokine family members have at least four conserved cysteine residues that form two intramolecular disulfide bonds. The chemokine subfamilies can be defined by the position of the first two of these cysteine residues.
The alpha (α) subfamily is also known as the CXC chemokines because they have one amino acid separating these first two cysteine residues. This group can be further subdivided based on the presence or absence of a glu-leu-arg (ELR) (SEQ ID NO:59) amino acid motif immediately preceding the first cysteine residue. There are currently at least five CXC-specific receptors, which are designated CXCR1 to CXCR5. The ELR+ chemokines bind to CXCR2 and generally act as neutrophil chemoattractants and activators, whereas the ELR− chemokines bind CXCR3 to CXCR5 and act primarily on lymphocytes.
In the beta (β) subfamily, which is also referred to as the CC chemokines, the first two cysteines are adjacent to one another and there are no intervening amino acids. There are currently 24 distinct human β subfamily members. The receptors for this group are designated CCR1 to CCR11. Target cells for various CC chemokine family members include most types of leukocytes, including monocytes, T lymphocytes, B lymphocytes, dendritic cells, natural killer cells, eosinophils and basophils.
There are also two known proteins having chemokine homology that fall outside of the α and β subfamilies. Specifically, lymphotactin is the lone member of the gamma (γ) class. It is also known as a C chemokine. This class of chemokines has lost the first and third cysteines. Thus, the lymphotactin receptor is designated XCR1.
Additionally, fractalkine, the only known member of the delta (δ) class, which is also known as a CX3C chemokine, has three intervening amino acids between the first two cysteine residues. Fractalkine is unique among chemokines because it is a transmembrane protein whose N-terminal chemokine domain is fused to a long mucin-like stalk. The fractalkine receptor is referred to as CX3CR1.